ABSTRACT:Autism spectrum disorders (ASDs) are a
group of developmental disorders marked by significant social,
communication, and behavioral impairments. The CDC estimates that 1 in
88 children has an ASD. While there is no cure for ASDs, there are both
nonpharmacologic and pharmacologic therapies available to aid in the
management of this condition. Management goals include minimizing the
core characteristics through educational interventions, treating
comorbidities commonly associated with ASDs, improving independence and
quality of life, and easing familial distress through education and
support. Pharmacists can assist patients and parents and/or caregivers
in a variety of ways to manage ASDs.

Surveillance data indicate a rise in identified autism
spectrum disorders (ASDs) from 1 in 150 children in 2000 to 1 in 88
children in 2008.1 ASDs, also known as pervasive developmental disorders, encompass a range of symptoms, skills, and levels of impairment, which explain their description as “spectrum” disorders.2
Within ASDs are autistic disorder; Asperger’s disorder (Asperger
syndrome); pervasive developmental disorder–not otherwise specified
(PDD-NOS); Rett’s disorder; and childhood disintegrative disorder.3

While ASDs occur in all racial, ethnic, and socioeconomic
groups, current epidemiological data suggest that prevalence is highest
among non-Hispanic white children.1 In addition, ASDs are more common among boys than girls, with an estimated prevalence of 1:54 compared to 1:252, respectively.1
With increasing prevalence, health care costs also rise. Annual medical
costs (average of $10,700 per child) are 4 to 6 times higher for a
child with an ASD compared to a child without.4,5

Etiology

While there is no definitive cause for ASD, research shows that both genetics and the environment play a role.2
Genetic causes include fragile X syndrome, which results from a single
genetic mutation causing intellectual disability, and tuberous
sclerosis, a rare genetic disorder that causes noncancerous tumor growth
in the brain and vital organs.2,6 Additionally, the presence
of a genetic link predisposes a child to ASD. In 9 out of 10 cases, if
one identical twin has ASD, the other twin also has ASD.7,8
In addition, there is 35 times the risk for siblings of a child with ASD
to develop the disorder. It is important to note that while there is an
increased familial risk, development of ASD is not definite.7,8

Research continues to explore environmental risks, such as
parental age, family medical conditions, complications during birth and
pregnancy, and the potential for ASD development.2 Vaccines
containing thimerosal are also at the center of the debate regarding ASD
risk. However, no evidence supports this theory, and the American
Academy of Pediatrics (AAP) supports childhood immunizations.9

Screening, Diagnosis, and Symptoms

A definitive diagnosis of ASD may be difficult to
determine, as the manifestations of ASD vary greatly. Notable
differences among children are onset of symptoms, symptom severity, and
the nature of the symptoms.10 Core ASD symptoms include
impaired social interaction skills, communication difficulties, and the
presence of repetitive or stereotyped behaviors, interests, and
activities.2,3

Children with an ASD do not achieve typical developmental skills in early childhood.2
Parents are often the first to detect such a delay, which may occur
prior to a child’s first birthday. However, other children may show
appropriate development until the second or third year of life. Loss or
reversal of normal development can also occur.2,10

Early identification of ASD is critical, as evidence
suggests that early identification and subsequent intervention may
result in significantly better outcomes.11 The AAP
surveillance algorithm for screening infants and young children for
developmental disorders suggests that developmental surveillance be
incorporated into every well-child visit though age 5 years.12
The five components of surveillance are eliciting and attending to
parental concerns about the child’s development; documenting and
maintaining a developmental history; making accurate observations of the
child; identifying the presence of risk and protective factors; and
documenting the process and findings.12

If concerns arise as a result of surveillance, further
assessment with developmental screening tests is warranted. The use of
screening tools to evaluate the child’s visual and hearing abilities,
early communication and language skills, and motor skills are tailored
to the child’s current age.12 In order to ensure that a child is meeting the appropriate developmental milestones (TABLE 1), screenings are administered at the 9-, 18-, and 24- or 30-month visits.12
If, at any time, a child fails to meet any milestone, further
assessment is necessary, as this indicates a high likelihood for the
presence of a developmental disability.13

The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria for the diagnosis of autistic disorder are provided in TABLE 2. Other disorders within the spectrum have different diagnostic criteria per the DSM-IV-TR.3
Of note, the DSM-V, scheduled for official release in May 2013, may
impose significant changes in the classification and diagnosis of ASDs.
The most considerable change comes with the labeling of ASDs. The
current DSM-IV-TR defines autistic disorder, Asperger’s disorder, and
PDD-NOS and considers them “autism spectrum disorders.” The DSM-V is
slated to replace the individual diagnostic labels of autistic disorder,
Asperger’s disorder, and PDD-NOS with one diagnostic label of autism spectrum disorder. Further distinction within the diagnosis, will be based on severity and noted by level 1, 2, or 3.14

Nonpharmacologic Therapies

ASDs require lifetime management. The primary goals of
nonpharmacologic management are to minimize the associated core
characteristics, improve the child’s independence and quality of life,
and ease family distress through education and support.11
Educational interventions are the foundation of ASD management and aim
to enhance communication, social, daily-living, play, and leisure
skills. Children should begin developmental interventions as soon as the
diagnosis of autism is considered. The AAP guidelines recommend
intensive educational interventions, such as active engagement of the
child for at least 25 hours per week year-round. Specific interventional
strategies are detailed in TABLE 3.11

Pharmacologic Therapies

Medications do not correct the core deficits associated
with ASD, but rather treat medical conditions and psychiatric
comorbidities that often accompany ASDs. Children with an ASD often have
additional conditions including sleep or sensory problems, seizures,
intellectual disability, mental disorders (anxiety, depression, or
attention-deficit/hyperactivity disorder [ADHD]), and gastrointestinal
(GI) disorders.2 One study reported that among children with
ASDs, about half had at least one of the three commonly co-occurring
conditions (ADHD, intellectual disability, or epilepsy).5

The prevalence of epilepsy among ASD patients ranges from
11% to 39%, with a higher prevalence in patients with comorbid mental
retardation and motor deficits.11 The onset of epilepsy in
ASDs is biphasic in distribution, peaking before 5 years of age and
again in adolescence. Selection of anticonvulsant medication and
treatment duration in children with epilepsy and an ASD does not differ
from routine childhood epilepsy treatment.11

Sleep disturbances are also common. It is important to
identify if the sleep disturbance has an identifiable etiology, and if
so, to correct it. If there is no identifiable cause, behavioral
interventions such as good sleep hygiene, restriction of daytime sleep,
and positive bedtime routines may be effective. While medications such
as antihistamines, alpha2-agonists, benzodiazepines,
trazodone, and newer sedative hypnotic agents are occasionally used in
the management of pediatric insomnia, the evidence for the use of these
agents in children with an ASD is lacking.11 Additionally, some evidence supports melatonin dysregulation and disruption of the circadian rhythm.15
A systematic review of randomized trials, assessing the efficacy of
oral melatonin versus placebo in children with developmental disorders,
found that while melatonin did not provide any significant improvements
in the total amount of sleep or the number of nighttime awakenings,
there was a statistically significant benefit for the time to sleep
onset.15 Therefore, it may be reasonable to try melatonin if sleep onset is the issue.

A range of behavioral symptoms often accompany ASDs,
including hyperactivity, short attention span, impulsivity,
aggressiveness, self-injurious behaviors, and temper tantrums.3
It is important to determine if the source of the behavior has an
identifiable etiology, such as constipation, headache, dental pain,
acute otitis media, or sinusitis, as this may instigate maladaptive
behavior.11 With no identifiable cause, a trial of medication
may be considered. While the use of psychoactive medications is common,
there is little evidence comparing the use of various agents for
symptom management associated with ASDs.11

Risperidone, an atypical antipsychotic, was the first
medication to receive FDA approval for the treatment of irritability
associated with autistic disorder in patients aged 5 to 16 years (TABLE 4). Risperidone demonstrated a 25% improvement on the aberrant behavior checklist (ABC) in 90% of patients in clinical trials.16
The ABC assesses drug and treatment effects using five scales,
including: 1) irritability, agitation, and crying; 2) lethargy and
social withdrawal; 3) stereotypical behavior; 4) hyperactivity and
noncompliance; and 5) inappropriate speech.17 Adverse events associated with risperidone include somnolence, sedation, increased appetite, and nausea.16

Another atypical antipsychotic, aripiprazole, is also
approved for the treatment of irritability associated with autistic
disorder in patients aged 6 to 17 years (TABLE 4). Efficacy was
determined by two 8-week trials in patients with autistic disorder with
significantly improved scores on the ABC and the Clinical Global
Impression-Improvement (CGI-I) scale.18 The CGI-I measures
change in clinical status since start of treatment using a 7-point
scale. Evaluation is based on symptomatic improvements from baseline and
impact of the changes on overall behavior and function.19
While aripiprazole may be a reasonable treatment option, the prescribing
information specifies that medication treatment for pediatric patients
with autistic disorder should only be initiated as part of a treatment
program that includes psychological, educational, and social
interventions. Adverse events include sedation, fatigue, vomiting,
somnolence, and tremor.18

Selective serotonin reuptake inhibitors (SSRIs), while not
FDA approved for ASDs, were studied for the treatment of repetitive
behaviors, obsessive-compulsive symptoms, aggression, anxiety, and
depressive disorder, with conflicting evidence.11,20 In a
12-week trial in adults with ASDs, fluoxetine started at 10 mg/day and
titrated to 80 mg/day as tolerated showed significantly greater
improvement in repetitive behaviors on both the Yale-Brown compulsion
subscale and the CGI-I scale.20 The Yale-Brown compulsion
subscale is a component of the larger Yale-Brown Obsessive Compulsive
Scale (Y-BOCS). When applied to ASD patients, the subscale measures the
severity and type of symptoms associated with compulsions, including
washing/cleaning, checking, repeating, counting, arranging, collecting,
and miscellaneous.21 The study found 1.4 side effects per
patient in the fluoxetine group compared to 0.6 in the placebo group.
The most common side effects experienced in the treatment group were
vivid dreams, dry mouth, insomnia, depressed mood, and nausea.20

In contrast, a 2009 trial targeting repetitive behaviors
in ASD patients aged 5 to 17 years compared citalopram to placebo and
found no significant difference in the response rate on the CGI-I or the
Yale-Brown compulsion scale.20,22 Citalopram was also associated with a higher incidence of adverse events (impulsiveness, hyperactivity, diarrhea, insomnia).22
It is important to note that the use of SSRIs require caution and
careful monitoring, as all carry a black box warning for increased risk
of suicidal thinking and behavior in individuals up to age 24 years.23

The use of complementary and alternative medicine (CAM) is common for patients with ASDs.11,24
CAM use in ASDs is classified as nonbiological or biological.
Nonbiological methods consist of music therapy and facilitated
communication, whereas biological interventions range from dietary
restrictions to GI treatments such as probiotics, vitamins, minerals, or
other natural products.11 There is currently insufficient
evidence to support the majority of CAM interventions for the treatment
of ASDs, as many CAM therapies have been inadequately evaluated or have
been shown to be ineffective.11

The Pharmacist’s Role

Pharmacists must ensure that the patient and/or parent or
caregiver understands each medication, its use, monitoring parameters,
and potential side effects and/or interactions, intervening as
necessary. Pharmacists should inquire about CAM use due to potential
interactions with prescription medications. Pharmacists can also serve
as a drug information resource, researching and evaluating available
evidence to assist patients in informed decision making.

Pharmacists should discuss not only medication use but
also ASDs and their management, and recommend resources for parents
and/or caregivers (TABLE 5). Taking the time to speak with the
parent and/or caregiver of a child with an ASD helps to develop a strong
relationship, which is necessary for the pharmacist in understanding
each patient’s needs and providing optimal care.

Finally, pharmacists should work as a member of the
patient’s health care team. With frequent patient contact, pharmacists
can assess response to therapy, communicate with medical providers, and
identify and explore medication nonadherence. Pharmacists may also work
with patients to develop goals to better manage the ASD and its
associated symptoms.